Exploring Heterogeneity in Pathogenic Bacterial Populations
The goals of the Davis Lab are to better understand how individual bacterial cells within a population contribute to disease, and to determine how to develop more effective therapeutics to target these populations.
Antibiotics have been utilized for decades in the treatment of bacterial infections, however antibiotic resistant infections are becoming increasingly more common, which limits the number of treatment options for patients. There is a critical need to develop new therapeutics, and to do this, we need to better understand exactly how bacteria survive and replicate within host tissues. Many factors have been identified that promote bacterial growth in the host, however it remains unclear if all the individual bacteria within a population produce these factors or only a subset of the bacterial population.
Our lab studies bacterial heterogeneity in a Yersinia pseudotuberculosis mouse model of infection, where we have discovered a surprising level of heterogeneity in gene expression within a single site of replication. Y. pseudotuberculosis replicates to form extracellular clusters of bacteria within host tissues, which are surrounded by host phagocytes. We have found that phagocytes drive a distinct gene expression profile in bacteria they contact at the periphery of these clusters, forcing peripheral bacteria to simultaneously detoxify antimicrobials and inactivate host phagocytosis. This protects the interior bacterial population, and presumably allows the interior subset of cells to replicate. Our future studies are focused on determining if the stress imparted on the peripheral cells slows their growth rate, and if this leads to antibiotic tolerance and survival following antibiotic treatment. We are also interested in studying the phagocyte population to determine how the host immune response can be manipulated to effectively limit bacterial growth, and promote clearance of the infection.
- Bacterial phenotypic heterogeneity
- Host-pathogen interactions
- Host phagocytes
- Impact of host-derived stresses on subsets of bacterial populations
- Antibiotic tolerance and susceptibility
- Host immune response manipulation
- Molecular microbiology and immunology
PATHOGENIC BACTERIAL POPULATIONS
Our lab uses fluorescent transcriptional reporters to identify distinct subpopulations of bacteria. This image shows Y. pseudotuberculosis replicating in the spleen; bacteria are responding to host cell contact (red) and nitric oxide (green), in response to host cells (blue).
Y. PSEUDOTUBERCULOSIS MICROCOLONY STRUCTURE
Y. pseudotuberculosis forms at least three subpopulations as it replicates in the spleen: 1) bacteria responding to direct neutrophil contact and nitric oxide from iNOS-producing host cells, 2) bacteria responding to nitric oxide diffusion, 3) bacteria replicating in the absence of either signal.
Our lab is also interested in exploring heterogeneity in other bacterial infection models, such as Staphylococcus aureus lesion formation in the mouse kidney. Image: S. aureus (red) replicates to form clustered lesions in the mouse kidney, surrounded by neutrophils (green) and additional host cells (blue).
Kim Davis, Ph.D., Assistant Professor
Department of Molecular Microbiology & Immunology
Johns Hopkins Bloomberg School of Public Health
615 N. Wolfe Street
W2705 (lab) E2628 (office)
Baltimore, MD 21205